Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in neonates as a sequella of prolonged oxygen and ventilation therapy for respiratory insufficiency associated with prematurity. Recent evidence suggests that proteolytic destruction of lung connective tissue is a major etiologic factor in the impaired lung development that is characteristic of the disease. Therapeutic exposure of infants to greater than 60% 02 for more than a week is associated with inactivation of alpha 1-proteinase inhibitor and uninhibited elastase in the lung secretions and elevated levels of degradation products of elastin (desmosines) in the urine. Studies conducted on neonatal rats exposed to 100% 02 during the period of major alveolarization of the lung have demonstrated a significant decrease in elastin concentration and impaired lung development further strengthening our hypothesis that hyperoxic exposure is a significant etiologic factor in impaired lung development of infants with BPD. We will use morphometric techniques to examine the concentration of lung elastin in autopsy specimens from infants with and without lung disease and will correlate these observations with clinical histories and biochemical data (lung secretion elastase and urine desmosines) obtained from these infants prior to death. We will continue to use the neonatal rat model to evaluate the influence of hyperoxic exposure on the developing lung. Specifically, we will quantitate, as a function of duration and intensity of oxygen exposure, lung elastin concentration, lung parenchymal development and pulmonary function and will subsequently determine the extent to which recovery occurs after cessation of 02 exposure. The role of the neutrophil (PMN) in hyperoxic-associated changes in elastin concentration and lung development will be assessed in a PMN- depleted animal model. Finally, in order to increase our understanding of the mechanisms involved in changes in elastin concentration and lung development associated with hyperoxic exposure, we will evaluate proteoglycans (PGs) and glycosaminoglycans (GAGs) in the extracellular matrix of lung parenchyma. We will then correlate distribution and rates of synthesis of specific PGs/GAGs and elastin with parenchymal development and identify specific changes in these parameters associated with hyperoxic exposure. We anticipate that the results of these studies will improve our understanding of normal lung development as well as the impairment due to hyperoxic exposure. In addition, these studies will allow us to further clarify the pathogenetic mechanisms of BPD and ultimately to facilitate therapeutic intervention.